1 June 2012. Dawn Velligan of the Texas Health Science Center, San Antonio, and Shitij Kapur of the Institute of Psychiatry, London, UK, chaired the 15 April opening plenary session of the 2012 Schizophrenia International Research Society meeting in Florence, Italy. The speakers reviewed the research on some of the non-pharmacologic treatments aimed at improving cognitive and social function in people with schizophrenia.

The first speaker, Christos Pantelis of the University of Melbourne, Australia, focused on imaging studies of cognitive remediation techniques (see, e.g., SRF related news story and Webinar). He noted long-standing data indicating that cognitive function is already compromised at disease onset and remains relatively stable through the ups and downs of psychosis. However, given the studies in the last several years reporting brain changes around the time of disease onset, some researchers wonder whether this is associated with loss of cognitive function.

He said that people with schizophrenia show more severe deficits in cognitive function than do even frontal lobe injury patients, yet it appears that not all of these deficits are present in the first episode. Pantelis said that cognitive remediation shows some consistent evidence for changing brain structure, though surprisingly not in the dorsolateral prefrontal cortex, but rather in medial and temporal cortical areas that subserve social cognition (e.g., the anterior cingulate cortex). He noted that these seem to be the areas that change early in illness.

Pantelis hypothesizes that some aspects of cognition are normal at disease onset, or mature normally but then deteriorate, and these might be the most amenable to improvement with cognitive remediation techniques. However, he also believes that cognitive remediation may need to happen during early to late adolescence to have this effect. Conversely, he suggests other cognitive functions never fully mature in schizophrenia, but could be addressed with cognitive adaptation methods, i.e., setting up "workarounds" in a person's environment. The latter may be the more valuable for patients with severe deficits.

Steffen Moritz of the University Medical Centre Hamburg-Eppendorf, Germany, discussed data on "meta-cognitive training," a method he developed with Todd Woodward of the University of British Columbia, Canada, to address delusional thinking in schizophrenia. He defined meta-cognition as "one's knowledge concerning one's own cognitive processes or anything related to them," or, more colloquially, "thinking about thinking." (see brief description at SRF's In Search of Collaborators page).

The computer-based training method (available for free in a number of languages) is intended to reduce jumping to conclusions from minimal data and also to decrease distortions in the perceptions of people with schizophrenia. Moritz reported that, in comparison to the cognitive remediation product COGPACK, the metacognitive training does produce significant results on these measures, and also reduces positive symptoms. In fact, he said, a single session significantly reduced jumping to conclusions and conviction of beliefs. More recently, the researchers have added a cognitive behavioral therapy (CBT) component, and preliminary data from a randomized controlled trial suggest superiority over COGPACK on a number of measures.

In the Q&A session, one audience member wondered whether the training, though targeting high-level cognition, such as beliefs, might not also be exerting beneficial effects by improving working memory or speed of processing. Moritz said that they would not expect this to be the case, and had not found evidence for such effects.

The next speaker, Douglas Turkington of the University of Newcastle, UK, discussed the effectiveness of CBT for positive and negative symptoms in schizophrenia. In his estimation, the evidence base from recent prospective studies shows that there is a long-term benefit of CBT, above and beyond the befriending of the patient by a professional. He notes that CBT and cognitive remediation appear to have comparable results, suggesting that there should be studies including both modalities.

However, these studies were all administered by experts, Turkington noted. What about mental health workers with less training? He presented new, unpublished data indicating that community nurses or case workers, trained and supervised regularly, could achieve lasting improvement in symptomatology and indicators of relapse. Turkington added the heartening possibility that CBT might benefit patients who refuse antipsychotic drugs for their positive symptoms. He reported data that indicated surprising benefits, not only on positive, but also negative symptoms. He interprets this as a function of people actively choosing a course of therapy and benefiting from something that resonates. These patients were not more likely to start to take antipsychotic drugs after the CBT.

Turkington believes that researchers will have to start thinking about which modalities fit best for different patients, for example, those with a strong delusional framework without hallucinations versus those who hear multiple voices but lack prominent delusions.

The final speaker, Michael Green of the University of California, Los Angeles, discussed social cognitive training for people with schizophrenia. He reviewed a large body of data indicating that social cognition, more than non-social cognition, is a major determinant of community functioning for people with schizophrenia. Empathy research, in particular, is an emerging focus in this area. Green made a distinction between lower-level emotional empathy ("I feel your pain") and higher-level, cognitive empathy ("I understand what you're experiencing"). Empathic accuracy depends on both, he said, and is valuable for patients.

In the clinic, Green and his collaborators have developed an intervention called Social Cognitive Skills Training (SCST) that targets emotional processing, social perception, attributional bias, and mental state attribution (or Theory of Mind). In a recent pilot trial, they found that the training significantly improves emotional processing, including facial affect perception and emotion management.

Following Green's lecture, the Chairs and the audience had a lively discussion about the difficulties of choosing between methods. Harking back to Turkington's lecture, one discussant suggested that it would depend on the patients and their current states. Chair Kapur wondered how it will be possible to implement proven, effective treatments on a large scale, and Green suggested that standardization may be a barrier both to research and clinical deployment. Turkington said that the key to broad implementation may be to make the methods more widely available for free. An audience member commented that there will be hard work ahead to convince psychologists in the community, who will be the main implementers, of the effectiveness of given therapies, since a significant portion of them, at least in the United States, believe that the patient-therapist relationship is more important to recovery of function than the particular specialized therapy. She suggested that, if a body like the American Psychological Association evaluated and vetted treatments, it might aid in implementation.—Hakon Heimer.

The field seems to be cautiously returning to look seriously at psychotherapeutic approaches. Paying attention to forms of cognition and affect has been a traditional form of therapy, and it seems foolish to ignore the clinical experiences of its many practitioners, despite conceptual problems of past work. We also have the benefits of studies indicating the effects of trauma on subsequent psychosis and developmental research on attachment and language that may mediate early neglect or trauma. Problems in development of TOM in insecure attachment may point to specific vulnerabilities.

The authors use cognitive training to enhance cognition and measure both cognitive functioning and the intactness of a neural network that they previous discovered. They find that they enhance cognition and improve regional brain activation. Further, social functioning is improved at a six-month follow-up.

Since the authors measured cognition and functionally relevant outcomes, these data again provide support for the usefulness of cognitive remediation for cognition and functioning, as well as show that these interventions directly impact critical neural networks. The integration of brain, cognition, and functioning makes a strong argument for the universal application of cognitive remediation in people with schizophrenia.

Dr. Subramaniam and colleagues deserve congratulations on an impressive study demonstrating that an extensive computerized cognitive training intervention appears to have effects on both brain physiology and performance on an untrained reality monitoring task—important evidence that the training does not only “teach to the test.” Further, the training appears to normalize the relationship between medial frontal activity and reality monitoring in patients, suggesting that the training has resulted in a reorganization of how patients are able to mobilize neural systems to meet the cognitive challenge. This result is important and adds to the evidence that the Posit Science approach may be valuable for people with schizophrenia. Adding to the importance of this result is the fact that, to date, there is no compelling, replicated evidence that any available pharmacological approach provides effective treatment for the cognitive impairments of schizophrenia. Indeed, given the apparent exodus of multiple major pharmaceutical companies from psychiatric treatment development research, the need to better understand the utility of psychosocial interventions is increasing as we search for answers for today’s patients and likely tomorrow’s as well.

No study is without problems in interpretation, and some arise here. For example, is it possible that the larger effect on the recognition of self-generated items versus externally presented items might be the result of potential ceiling effects in the externally presented condition? In addition, the interpretation of the social functioning results might have been clearer if change in BOLD signal had been correlated with change in social functioning. The current result: no overall change in social function, but correlation between BOLD signal at the end of training and social functioning level at six months. This makes it hard to interpret training-related improvement in medial prefrontal activity as causing the changes in social functioning, basically missing the link that goes directly from treatment condition to outcome.

Lastly, it remains unclear exactly how the Posit Science program works at a neural level. Clearly the approach was designed to target lower-level sensory-perceptual processes with the goal of increasing the fidelity and precision of the inputs to higher-order systems. It would certainly make sense that the gradual training approach, which titrates difficulty level, does indeed work this way. Other non-incompatible possibilities deserve to be considered. Might the dense training approach serve as a kind of attentional and strategy training just as much as perceptual training? That is, patients learn how to get things “right.” One could imagine that this could occur because specific neural populations involved in task performance become more efficient, their task-relevant “receptive fields” become more precise. Alternatively, it is also be possible that higher-order attentional functions are also becoming trained to more efficiently modulate lower-level systems. And it might be easier to understand the type of generalization effects seen in this study if the training inadvertently also had benefits to task general cognitive systems that may be brought to bear on many untrained tasks. It remains for future work to see which understanding is more accurate.

In the meantime, the contribution of the Vinogradov team deserves recognition for an ambitious study, a potentially important and intriguing finding, and providing a ray of hope in an otherwise pretty dark treatment development landscape.

Comment by: Robert McCarleySubmitted 7 March 2012
Posted 8 March 2012 I recommend the Primary Papers

Very exciting and hopeful data, especially in this patient population who had been ill nearly 20 years. These data argue strongly for similar trials at other sites.

From a scientific point of view, it will be interesting to see if these functional changes will be accompanied by structural alterations of increased MRI gray matter, compatible with plasticity and increased dendritic and synaptic elements.

Most of the speakers at the SIRS session spoke of an involvement of oxytocinergic dysfunction in social deficits of schizophrenic patients. But oxytocin may be involved in the pathogenesis of schizophrenia in many other ways. For example, the mentioned improvement of odor discrimination may be caused by an increase in neurogenesis in the olfactory bulb. Oxytocin enhances neurogenesis, increases BDNF levels (Ayfer et al., 2011), and preserves granule cells from the deleterious effects of stress hormones (Leuner et al., 2012). Perhaps insufficient neurogenesis is the core component of schizophrenia pathogenesis. Tamminga et al. (Tamminga et al., 2010) have formulated a model according to which reduced neurogenesis in the dentate gyrus produces hyperactivation of the CA3 region and generates inappropriate associations, misinterpretation of events, false or illogical memories, and susceptibility to psychosis.

Oxytocin can also activate hippocampal GABAergic interneurons and inhibit excitation of pyramidal cells (Zaninetti et al., 2000). In the adult dentate gyrus, GABA is excitatory in newborn neurons due to their high intracellular Cl- concentration (Aimone et al., 2010). Oxytocin promotes an inhibitory action of GABA by reducing activity of the chloride co-transporter NKCC1 (Mazzuca et al., 2011). Perhaps oxytocin insufficiency results in excitotoxic damage of immature granule cells, especially during stress. Lodge and Grace (Lodge and Grace, 2011) have demonstrated that psychological stress and hyperactivation of the anterior hippocampus can result in enhanced activity of dopamine neurons and psychotic symptoms. Since oxytocin diminishes both cortisol and behavioral responses to stress (Kosfeld et al., 2005), its administration to patients with schizophrenia could be beneficial.

The notion that cognitive remediation is effective in producing cognitive and functional gains in established schizophrenia (Wykes et al., 2011), and produces other gains such as changes identified in brain imaging (e.g., Wykes et al., 2002) is unsurprising. But the paper on remediation in adolescent rats by Lee and colleagues provides results that the authors do consider surprising, and could lead to further extensions of cognitive remediation to those who are "at risk" for disorders such as schizophrenia. This is because of the procognitive effects of providing training in youthful rats.

Procognitive effects of experience-based training are not, however, surprising. The authors quote research showing that there are functional changes with training—the one that springs to my mind is London taxi drivers whose hippocampi are larger following their "training" for The Knowledge—an all-roads-in-London test. So why are the authors surprised? Perhaps it is because the results may have further implications for treatment and prevention, but only if followed up in those who are “at risk,” a notion that has produced much heat and not much light in the annals of SRF. We have been optimistic about the possibility of change in prodromal patients using cognitive behavioral therapy, but that hope has not yet been justified in the current research. It may be that this form of experience-based learning is of greater help in the prodromal group than the traditional cognitive behavioral therapies. It may also be that we need to begin our interventions in school by identifying those who are cognitively at risk for many different future problems, not just schizophrenia.

The results also suggest that even when there is a known lesion, it is possible to normalize behavior as well as produce some correlated neuronal change. This is exciting, as it opens up the possibility of finding cures, if not for the whole disorder at least for some of the problems or symptoms of schizophrenia. All this can be produced by a non-pharmacological intervention. This is something that will surely excite the providers of healthcare, as the cost-benefit would be very high if the future health costs for these patients were reduced through such means.

In their new Neuron article, Lee and colleagues from Andre Fenton’s group at NYU report that spatial cognitive control deficits in a rat model of schizophrenia can be prevented through a ratish analogue of cognitive remediation therapy during adolescence. The importance of early intervention has been one of the hottest debates in applied schizophrenia research; the current findings suggest a basic mechanism in support of such efforts.

What is remarkable about the Fenton study is how small a training “dosage” was required to lead to markedly different adult performance. Two days of training about five weeks after birth led to marked changes in the rats’ capacity to use spatial cognitive control eight to nine weeks after birth.

Rats were sacrificed at the end of the experiment, allowing the researchers to examine the extent to which the initial lesion had affected brain development. The initial lesions dramatically altered hippocampal development. Despite this, lesioned rats who received training did not show any observable difference in brain morphology in adulthood compared to lesioned rats who did not receive training. That is to say, the integrity of the hippocampus measured grossly did not predetermine that rats would perform poorly on the spatial cognitive control task—if they received training. However, subsequent analysis demonstrated that phase synchronization between the hippocampus and prefrontal cortex (which rats possess, albeit not in extremis) was compromised in the lesioned rats who did not receive training, but was recovered in those that did receive training.

Thus, the data suggest that fundamentally important circuitry can be guided through training that is relevant for later cognitive functioning.

What is absent is evidence for the specialness of adolescent intervention. This seems to be assumed from previous work rather than the result of comparisons of implementing the intervention at different ages.

It’s also interesting to note that hippocampal lesion models are generally evaluated using memory-related tasks. Fenton’s task presents something of a hybrid. The spatial cognitive control paradigm used is appropriately adapted to the species in question, but in the abstract it has features similar to that of the Stroop task. In Fenton’s active place avoidance task, there is a dominant channel for responding on which the rat is over-trained, like the Stroop task's word reading component on which most people reading this text have been over-training. There is also a subordinate channel for responding, with which the rat is familiarized, something like color naming on the Stroop task. However, a key aspect of the manipulation is the inability to learn a new zone to avoid, which may be more akin to perseveration than to Stroop performance. Rotation of shock zone to a new location is described as task transference, but since the original learning was a source of interference (and needed to be inhibited) in the subsequent task, I’m not sure I agree with this description.

This work will be warmly received by a large number of advocates who are pushing for interventions earlier in the risk period. One advantage the authors had compared to those in the clinical schizophrenia field is that they knew which of their rats were strongly exposed and were therefore at the highest risk. While our screening tools have been honed over the past decade, they still have a high false-positive rate. One can take some solace, though, that cognitive remediation is unlikely to have extensive negative side effects. Except, perhaps, boredom.

I am always a little skeptical of animal models of psychosis or schizophrenia, which are pretty high-order disturbances and seem very specific to humans. If this model has some validity, the preventive therapy in humans would be more akin to cognitive remediation therapy rather than cognitive therapy per se, which has more CBT links or connotations.

Lee et al. report exciting new data in support of the neurodevelopmental hypothesis of schizophrenia and the plausibility of the early intervention that might prevent the emergence of schizophrenia symptoms. Lee and colleagues used a neonatal ventral hippocampal lesion in rats as a model of schizophrenia.

First, using the active place avoidance task with carefully designed control tasks, they showed that the animals with neonatal lesions are cognitively impaired as adults, consistent with the results of the previous studies (see Tseng et al., 2009, for review). Next, they examined whether training of the lesioned animals in adolescence would prevent the emergence of these abnormalities. They exposed the animals to a series of cognitive tests and found that, indeed, the neonatally lesioned rats that acquired additional training as adolescents showed improved cognition in adulthood. Moreover, specific measures of neural function were also improved. The authors recorded local field potentials in the hippocampi and found that the neonatally lesioned animals showed deficits in interhippocampal synchrony, the findings similar to the changes reported in patients with schizophrenia. Adolescent cognitive training normalized interhippocampal synchrony and improved performance on the cognitive tasks in the neonatally hippocampally lesioned rats. Finally, to gain more insight into the mechanisms of these changes, the authors measured cortical thickness and parvalbumin protein content, but these parameters were not informative about the benefits of cognitive training in this animal model of schizophrenia.

The results of this study support the notion that schizophrenia is a neurodevelopmental disorder characterized by discoordinated neural networks, and provide critical evidence for the benefits of early behavioral intervention. Although we still do not fully understand the pathophysiological mechanisms underlying schizophrenia, or the mechanisms responsible for the improvements due to cognitive training, this work certainly offers a potential new therapeutic tool in the form of preemptive cognitive therapy.